Abstract 2592: Aurora kinase is an actionable target in low molecular weight cyclin E induced mammary tumors
Authors: Said Akli, Amriti R. Lulla, Francisco R. Saenz, Fuchenchu Wang, Natalie W. Fowlkes, Tuyen Bui, Yan Wang, Sofia Mastoraki, Min Jin Ha, Kelly K. Hunt, Khandan Keyomarsi
Journal: Cancer Research (2022)

Abstract Background: Cyclin E, a key mediator for G1 to S transition, has unique tumor-specific deregulation in multiple malignancies including breast, ovarian, and colorectal cancers. Our group previously reported that the oncogenic roles of cyclin E are primarily a consequence of the accumulation of several truncated forms, collectively termed low-molecular-weight cyclin E (LMW-E). LMW-E isoforms provide a growth advantage by inducing early G1 to S phase transition, genomic instability, increased cell proliferation and metastasis, as shown in breast cancer cell lines and transgenic mouse models. Clinically, assessment of 2,500 breast cancer patients has revealed that LMW-E expression in tumors is associated with a high risk of recurrence across all subtypes. Further, LMW-E expression is an independent predictor of response to neoadjuvant chemotherapy. Current gaps in knowledge in the field that remain pertain to (i) if LMW-E is an early or late event in oncogenesis (ii) if it is required for both the initiation and maintenance of mammary tumors, (iii) the secondary oncogenic events induced by LMW-E and if these events can be targeted therapeutically. Methods: To address the above questions, we generated three tetracycline-inducible LMW-E (TLMW-E) transgenic model systems with expression of mammary specific human LMW-E in different genetic backgrounds: These include a bi-transgenic model (MMTV-rtTA and Tet-O-LMW-E), a tri-transgenic (bi-transgenic in a p53+/- background) and quad-transgenic (tri-transgenic in a cyclin E knockout background). For each model, TLMW-E mediated tumor initiation, progression and metastasis, is reported as a function of time. Molecular analysis of the mammary gland and tumors are performed to identify therapeutic vulnerabilities of LMW-E expressing tumors. Results: TLMW-E dependent alterations in cell cycle are early and irreversible events, leading to increased proliferation starting from the hyperplastic stages of tumor development. Transcriptomic analysis of TLMW-E derived mammary tumors revealed significant alterations in the G2/M transition and E2F signaling. We also interrogated the role of G2/M regulator, Aurora Kinase A (AURKA), that was altered in a TLMW-E dependent fashion. Correlative analysis using publicly available datasets confirmed the linked co-overexpression of AURKA and cyclin E in basal breast cancer as compared to normal breast tissue. In vivo studies using the AURKA inhibitor, alisertib, showed that mammary tumors were sensitive to AURKA inhibition as a single agent and in combination with chemotherapy, as a function of LMW-E expression. Conclusion: Collectively, our data suggest that the induced expression of LMW-E is tumorigenic, independent of p53 or endogenous cyclin E status and responsive to treatment with an AURKA inhibitor. Citation Format: Said Akli, Amriti R. Lulla, Francisco R. Saenz, Fuchenchu Wang, Natalie W. Fowlkes, Tuyen Bui, Yan Wang, Sofia Mastoraki, Min Jin Ha, Kelly K. Hunt, Khandan Keyomarsi. Aurora kinase is an actionable target in low molecular weight cyclin E induced mammary tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2592.